The contribution of bone marrow macrophages to Acute Myeloid Leukemia growth

Abstract

Acute myeloid leukemia (AML), is one of the deadliest forms of cancer. It has been relying on chemotherapy as its primary treatment for the past three decades. However, relapse after therapy (50-90%) leads to the development of an aggressive form of leukaemia, resistant to current treatment. While immunotherapies are on the rise to treat most cancers, its use in AML is highly challenging due to the lack of tumour cell signature and increased side effects. A better understanding of the disease and its interaction with the immune system is essential to develop targeted therapies with lower side effects and prevent relapse occurrence. Using a combination of microscopy and high-dimension flow analysis, I identified two functionally and phenotypically distinct populations of macrophages, interacting with malignant cells. The first population named Haematopoiesis-supportive macrophage (HSM), expressed Vascular cell adhesion molecule 1 (VCAM-1), a marker associating them with the retention of healthy haematopoietic cells. These cells were found to be lost first during AML. The second population, AML-associated macrophages (AAMs), expressed Signal regulatory protein α (SIRPα) and Programmed death-ligand 1 (PDL-1), two markers important in the inhibition of the immune response in cancer. These cells were found to be enriched at early AML. Combining these results with single cell RNA-sequencing and functional in vitro assays, I found that AAMs were efferocytic cells, capable of phagocytosing AML cells and inhibiting activated T cells. By targeting these cells using different genetic and pharmacological techniques, I was able to show that the depletion of AAMs led to reduced AML growth while the accumulation of AAMs was associated with faster AML growth. Together, this thesis provides an insight into the phenotype and function of different macrophage populations present in the bone marrow and their involvement in AML. This work opens up new avenues for further research and novel therapeutic targets for immunotherapy.